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Stem Cell Marker Expression in Early Stage Colorectal Cancer is Associated with Recurrent Intestinal Neoplasia

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Abstract

Background

Colorectal cancer (CRC) ranks second in cancer deaths worldwide and presents multiple management challenges, one of which is identifying high risk stage II disease that may benefit from adjuvant therapy. Molecular biomarkers, such as ones that identify stem cell activity, could better stratify high-risk cohorts for additional treatment.

Methods

To identify possible biomarkers of high-risk disease in early-stage CRC, a discovery set (n = 66) of advanced-stage tumors were immunostained with antibodies to stemness proteins (CD166, CD44, CD26, and LGR5) and then digitally analyzed. Using a second validation cohort (n = 54) of primary CRC tumors, we analyzed protein and gene expression of CD166 across disease stages, and extended our analyses to CD166-associated genes (LGR5, ASCL2, BMI1, POSTN, and VIM) by qRT-PCR.

Results

Stage III and metastatic CRC tumors highly expressed stem cell-associated proteins, CD166, CD44, and LGR5. When evaluated across stages, CD166 protein expression was elevated in advanced-stage compared to early-stage tumors. Notably, a small subset of stage I and II cancers harbored elevated CD166 protein expression, which correlated with development of recurrent cancer or adenomatous polyps. Gene expression analyses of CD166-associated molecules revealed elevated ASCL2 in primary tumors from patients who recurred.

Conclusions

We identified a protein signature prognostic of aggressive disease in early stage CRC. Stem cell-associated protein and gene expression identified a subset of early-stage tumors associated with cancer recurrence and/or subsequent adenoma formation. Signatures for stemness offer promising fingerprints for stratifying early-stage patients at high risk of recurrence.

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Acknowledgements

Research reported in this publication was supported by the National Institute of Digestive Disease U01DK085525 (MHW); Knight Cancer Institute Pilot award (VLT); and the Knight Cancer Institute P30CA069533.

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Author notes

  1. Brett S. Walker and Luai R. Zarour contributed equally.

Authors and Affiliations

  1. Department of Surgery, OHSU, 3181 SW Sam Jackson Park Rd, L619, Portland, OR, 97239, USA

    Brett S. Walker, Luai R. Zarour, Nicole Wieghard, Kevin Billingsley & V. Liana Tsikitis

  2. Department of Cell, Developmental, and Cancer Biology, OHSU, 2720 S Moody Ave., KR-CDCB, Portland, OR, 97201, USA

    Alexandra C. Gallagher, John R. Swain & Melissa H. Wong

  3. Kaiser Permanente Northwest Center for Health Research, 3800 N. Interstate Ave., Portland, OR, 97227, USA

    Sheila Weinmann

  4. Department of Pathology, OHSU, 3181 SW Sam Jackson Park Rd, L-113, Portland, OR, 97239, USA

    Christian Lanciault

  5. Knight Cancer Institute, Oregon Health & Science University, 2720 S Moody Ave., Portland, OR, 97201, USA

    Kevin Billingsley, V. Liana Tsikitis & Melissa H. Wong

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  1. Brett S. Walker
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Correspondence to V. Liana Tsikitis or Melissa H. Wong.

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Informed consent was obtained from all individual participants included in the study. Study was approved by the Institutional Review Board from both institutions (OHSU and Kaiser Permanente) prior to conducting any review of archived tissue or patient data.

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Walker, B.S., Zarour, L.R., Wieghard, N. et al. Stem Cell Marker Expression in Early Stage Colorectal Cancer is Associated with Recurrent Intestinal Neoplasia. World J Surg 44, 3501–3509 (2020). https://doi.org/10.1007/s00268-020-05586-z

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